WO2008067273A2

WO2008067273A2 - Implantable devices with therapy delivering surfaces and methods

Info

Publication number: WO2008067273A2
Application number: PCT/US2007/085570
Authority: WO
Inventors: Jing Tang; S. Eric Ryan
Original assignee: Cornova, Inc.
Priority date: 2006-11-28
Filing date: 2007-11-27
Publication date: 2008-06-05
Also published as: WO2008067273A3

Abstract

An implantable device is provided having a therapy-delivering surface thereon. Upon deployment, the surface elutes a therapeutically effective dosage of dipyridamole sufficient to reduce the likelihood of thrombosis, restenosis, or both. A steady dosage of dipyridamole is delivered so as to maintain between at least about.000275 to.001 micrograms of the drug per square millimeter of tissue directly surrounding the device for a target therapy period. The device can be a cardiovascular stent in which the therapy is applied during at least the initial 7 days after deployment.

Description

IMPLANTABLE DEVICES WITH THERAPY DELIVERING SURFACES AND METHODS

RELATED APPLICATIONS

This application claims the benefit of U.S. Patent Application Number. 60/867,438 filed November 28, 2006, entitled "Systems and Compositions of Biocompatible Surfaces," and U.S. Patent Application Number 60/889,655 filed February 13, 2007, entitled "Biocompatible Polymers, Polymer Tie-Coats, Methods Of Making And Using The Same, And Products Incorporating The Polymers," the entire contents of each of which is herein incorporated by reference.

FIELD OF THE INVENTION

This invention generally relates to drug therapy delivery systems in connection with the tissue-to-surface interface of implantable devices. Such systems include polymer-based coatings and drug eluting polymer coatings for intravascular implants having, in particular, anti-thrombotic and anti-stenotic characteristics.

BACKGROUND OF THE INVENTION.

A critical aspect of medical implants, including stents, are their long- and short-term effectiveness and safety. Potential adverse reactions to placement of intravascular implants include inflammation, restenosis (the narrowing of a blood vessel due to the undesired tissue growth about the implant) and thrombosis (the formation of a blood clot within the vessel). Thrombosis, in particular, can lead to serious complications and death such as from a resulting heart attack. Therefore, in addition performing their primary function (e.g. prosthesis), implants preferably include surfaces that reduce the risk of the above-identified adverse reactions. A number of surface technologies have been developed for avoiding restenosis and thrombosis, including various biocompatible metallic surfaces and polymer-based drug eluting surfaces. Presently adopted metal surfaces include corrosion-resistant noble types such as gold, platinum, silver, and alloys thereof. Restenosis rates resulting from bare-metal surfaces over a period of about 36 months have been observed to occur in about 20% to 25% of stent applications and thrombosis rates have been observed to be between about .5% and 1%. In order to decrease the likelihood of these complications, surfaces have been developed that elute drugs specifically targeting, for example, restenosis and/or thrombosis. These surfaces typically include porous polymer-based coatings prepared and mixed in a manner to time-release an amount of a selected drug upon insertion into a vessel. Various drug eluting technologies have shown promise by significantly reducing stenosis (e.g. down to rates of about 6.4%), however, some current studies have suggested that many of these drug eluting technologies increase the rate of the more damaging thrombosis events, particularly later- term (3-7 days and longer) thrombosis, to about 1.5%.

An extensive catalog of drugs and combinations thereof have been suggested for use on stents and other medical implants. The desired effects of such drugs typically include an anti-proliferative effect to prevent the growth of cells along the vessel walls (e.g., to prevent restenosis) such as through the use of, for example, sirolimus, paclitaxel and their structurally-related derivatives. Other desired effects include anti-coagulant/anti-platelet activation properties (e.g., to prevent thrombosis) through the use of, for example, heparin.

While many conventional drugs provide short-term positive effects against restenosis or thrombosis, some studies suggest that, over the long-term (e.g., between 7 days and several years), the effects may be opposite to those intended. The delivery of drug from most eluting systems is complete after about 30 days, potentially leaving an implant that isn't fully biocompatible or around which tissue hasn't fully or properly healed. Dissections of previously used drug-eluting stents in patients have suggested that the high toxicity of typical drugs (often traditionally developed as cell-cycle inhibitors with anti-cancer benefits) over the long-term may prevent healthy healing and cause further damage to the vessel walls subsequent to deployment of a stent in them.

Ideally, after deployment, endothelial cells about the stent and vessel are re-formed in order to provide a smooth vessel lumen surface through which blood passes. Cell cycle inhibitors, including those previously disclosed, can potentially interfere with this process, leaving a roughened lumen surface. After the elution of the drugs has primarily expired, the absence of proper healing and lack of further anti-thrombotic effects to the vessel walls may finally result in drastic coagulation/platelet-activation in the area and result in thrombosis and serious consequences therefrom (e.g., heart attacks). In order to combat such occurrences, many doctors will prescribe a long-term or life-long dosage of anti-coagulant drugs (e.g. Clopidogrel). However, these drugs include their own risks and drawbacks, such as the potential for uncontrolled bleeding and significant costs. Thus, surface elution systems with dosages of therapy-delivering drugs are needed that provide both the short-term anti-stenotic effects and both short and long-term anti-thrombotic effects without the risks and costs associated with conventional drug elution systems.

SUMMARY OF THE INVENTION

An aspect the invention provides a therapeutic surface coating system for implantable devices. The coating system can include one or more polymer-based layers over the surface of an implantable structure. In an embodiment of the invention, a surface layer is provided which elutes a therapeutically effective dosage of dipyridamole that, in comparison to a bare metallic surface, can significantly reduce the likelihood of thrombosis and/or restenosis along the implantable structure upon deployment. The implantable structure can be, for example, a stent with an underlying metallic flexible substrate. In an aspect of the invention, a surface coating system for implantable devices is provided including an implantable structure having a surface thereon and one or more coatings layered upon the surface. The coatings include a surface layer manufactured to elute, upon deployment of said implantable structure within a human, a therapeutically effective dosage of dipyridamole sufficient to significantly reduce the likelihood of at least one of thrombosis or restenosis along said implantable structure. In an embodiment, the implantable structure is a stent.

In an embodiment, the effective dosage of dipyridamole includes maintaining about .000275 to .001 micrograms of dipyridamole per square millimeter of tissue surface that directly encompasses the implantable structure. In an embodiment, the surface layer elutes the effective dosage at a rate of at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of a target therapy period. In an embodiment, the surface layer elutes the effective dosage at a rate of between about .002 and .008 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of a target therapy period. In an embodiment, the target therapy period includes at least the initial 7 days after deployment of the implantable structure.

In an embodiment, the surface layer elutes the effective dosage at a rate of between at least about .01 to .08 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of at least a portion of the target therapy period. In an embodiment, the portion of the target therapy period includes at least the first 3 days after deployment of the implantable structure. In an embodiment, the target therapy period includes at least the initial 7 days after deployment of the implantable structure during which period a rate of at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area is eluted during each 10 hour interval.

In an embodiment, the surface of the implantable structure does not significantly elute any other therapeutically active agent other than the therapeutically effective dosage of dipyridamole.

In an aspect of the invention, a method of delivering an implantable device includes providing an implantable structure having a surface thereon, placing the implantable structure into a living subject, eluting from the surface of the implantable structure a therapeutically effective dosage of dipyridamole, the dosage being sufficient to significantly reduce the likelihood of at least one of thrombosis or restenosis along the implant structure. In an embodiment, the implantable structure is a stent. In an embodiment, eluting the therapeutically effective dosage of dipyridamole maintains about .000275 to .001 micrograms of dipyridamole per square millimeter of tissue surface directly encompassing the implantable structure.

In an embodiment, eluting a therapeutically effective dosage includes eluting at least about .0022 to .008 micrograms of dipyridamole per square millimeter of the tissue surface area during each 10 hour interval for a target therapy period.

In an embodiment, eluting a therapeutically effective dosage includes eluting between about .0022 to .008 micrograms of dipyridamole per square millimeter of the tissue surface area during each 10 hour interval for a target therapy period.

In an embodiment, the target therapy period includes at least the initial 7 consecutive days after deployment of the implantable structure.

In an embodiment, eluting a therapeutically effective dosage includes eluting between about .01 to .08 micrograms or more of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval for at least a portion of said target therapy period.

In an embodiment, the at least a portion of the target therapy period includes the initial 3 consecutive days after deployment of said implantable structure.

In an embodiment, the target therapy period includes at least the initial 7 days after deployment of the implantable structure during which at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area is eluted during each 10 hour interval. In an embodiment, the implantable structure does not significantly elute any other therapeutically active agent other than the therapeutically effective dosage of dipyridamole.

In an aspect of the invention, a method of stenting a vessel is provided that includes the steps of providing a stent having a surface thereon, placing the stent into the vessel, eluting dipyridamole from the surface of the stent at a rate of least about .0022 to .008 micrograms of dipyridamole per square millimeter of inner vessel surface area surrounding the stent during each 10 hour interval for a target therapy period.

In an embodiment, the target therapy period includes the initial 7 days after deployment. In an embodiment, dipyridamole is eluted at a rate of about .01 to .08 micrograms of dipyridamole per square millimeter of inner vessel surface area surrounding the stent during each 10 hour interval for a period of at least 3 days.

In an aspect of the invention, an implantable device is provided that includes a substrate and a polymer-based layer coating the substrate. The polymer-based layer has a dipyridamole-to-polymer ratio of at least about 20% by weight. In an embodiment of the invention, the polymer-based layer has a dipyridamole-to-polymer ratio of between about 20% and 30% by weight.

In an aspect of the invention, a method for eluting a locally effective dosage of dipyridamole or its derivatives from a vessel implant is provided. An embodiment of the method includes determining the approximate minimum concentration of dipyridamole in blood from an established systemic dosage for a targeted region (e.g., the cardiovascular region), translating the concentration of diyridamole in blood into an amount of dipyridamole per unit area of targeted vessel tissue (wherein substantially all of the dipyridamole in blood at an instant of time and encompassed by the tissue walls is assumed to be absorbed), and adapting a polymer-based drug-eluting coating for an implant such that it elutes a sufficient amount of dipyridamole to maintain the previously calculated dipyridamole per unit area concentration for a prescribed period of time.

BRIEF DESCRIPTION OF THE DRAWINGS

The structure, operation, and methodology of the embodiments of the invention, together with other objects and advantages thereof, may best be understood by reading the following detailed description, including that which is in connection with the drawings. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

Figs. 1 A-IB show an elution profile of dipyridamole from a polymer-coated stent in accordance with an embodiment of the invention. Fig. 2 A is an illustrative side view of a stent in accordance with an embodiment of the invention. Fig. 2B is an illustrative transverse cross-sectional view of a strut of the stent of Fig. 2 A, taken along section lines I-F of Fig. 2 A.

Fig. 3 A is a cross-sectional view of a vessel segment from a study in which a bare stainless steel stent was placed in a rat aorta. Fig. 3B is a cross-sectional view of a vessel segment from a study in which a stent coated with a dipyridamole-eluting polymer was placed in a rat aorta.

Fig. 3C is a cross-sectional view of a vessel segment from a study in which a stent coated with a non-drug-eluting polymer was placed in a rat aorta.

Fig. 4 is a chart from a study including comparative measurements of neo-intimal growth associated with stents of various surface types placed in rat aortas.

DETAILED DESCRIPTION

The accompanying drawings are described below, in which example embodiments in accordance with the present invention are shown. Specific structural and functional details disclosed herein are merely representative. The invention may be embodied in many alternative forms and should not be construed as limited to the example embodiments described herein.

It will be understood that the drawings are not intended to accurately reflect relative proportions of layer thicknesses but rather to illustrate the general order of layer positions. Accordingly, specific embodiments are shown by way of example in the drawings. It should be understood, however, that there is no intent to limit the invention to the particular forms disclosed herein, but to the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the claims.

It will be understood that, although the terms first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are used to distinguish one element from another. For example, a first element could be termed a second element, and, similarly, a second element could be termed a first element, without departing from the scope of the present disclosure. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

It will be understood that when an element is referred to as being "on," "adjacent," "connected to," or "coupled to" another element, it can be directly on, connected to or coupled to the other element or intervening elements may be present. In contrast, when an element is referred to as being "directly on," "directly adjacent," "directly connected to," or "directly coupled to" another element, there are no intervening elements present. Other words used to describe the relationship between elements should be interpreted in a like fashion (e.g., "between" versus "directly between,"etc). It will be understood that the term "directly on," as used herein, is intended to describe situations where there is a substantial molecular contact between two elements or layers, for example, between a polymer layer and a tie-coat directly underneath, or between a tie-coat directly on a substrate.

It will also be understood that an identified drug or compound (e.g. dipyridamole) is intended to encompass various analogs and derivatives in which a substitution would be apparent to one of ordinary skill in the art.

Various embodiments provide biocompatible coatings for implants having antithrombotic and anti-stenotic benefits. In an aspect , a drug delivery system that elutes effective dosages of dipyridamole is provided so as to further improve the biostability of an implant surface. Dipyridamole, in various dosages, can provide anti-thrombotic benefits (CW. Kopp, et al., "Parameters of the tissue factor pathway with coumadin/dipyridamole versus ticlopidine as adjunct antithrombotic-drug regimen in coronary artery stenting," Blood Coagul Fibrinolysis, Vol. 14(4):379-86 (2003), the entire contents of which is herein incorporated by reference). Dipyridamole has also been shown to have effective anti-stenotic benefits (J.P. Singh, "Dipyridamole directly inhibits vascular smooth muscle cell proliferation in vitro and in- vivo: implications in the treatment of restenosis after angioplasty", J Am Coll Cardiol., Vol. 23(3):665-71 (March 1994), the entire contents of which is herein incorporated by reference). In certain studies, dipyridamole has shown to have even a greater anti-proliferative effect than paclitaxel (SJ Kim et al., "Arterial and venous smooth-muscle cells differ in their responses to antiproliferative drugs," J Lab Clin Med. Vol. 144(3): 156-62 (2004)). Clinically, dipyridamole has been delivered systemically to reduce postoperative thromboembolism, particularly in patients with artificial heart components and has been used as a vasodilator in diagnostic assays. In an embodiment , a controlled dosage of dipyridamole is eluted from an implant surface so as to work at least in an anti-coagulant/anti-platelet-activation capacity, thus providing effective anti-thrombotic benefits. Dipyridamole is known to provide anticoagulant/anti-platelet activation benefits in systemic dosages of, for example, between about .5 and 1.9 micrograms per milliliter volume of blood (e.g., see http://www.rxlist.com/cgi/generic3/aggrenox_cp.htm for the clinical pharmacology of the dipyridamole-based anti-thrombotic drug Aggrenox). Dipyridamole has the formula 2,2',2",2'"-(4,8-dipiperidinopyrimido[5,4-d]pyrimidine-2,6-diyldinitrilo)tetraethanol or, using alternative nomenclature, 2,6-bis(diethanolamino)-4, 8-dipiperidinopyrimido- [5,4d]pyrimidine. Other dipyridamole derivates may be appropriate, with accordingly modified dosages, including a photoreactive version consisting of a triply protected dipyridamole and photoreactive 4-azidobenzoyl group ("Synthesis of a New Photoreactive Derivative of Dipyridamole and Its Use in the Manufacture of Artificial Surfaces with Low Thrombogenicity", Bioconjugate Chem., Vol. 8(3):296-303 (1997), the entire contents of which is herein incorporated by reference). Additional appropriate derivatives are described in U.S. Patent No. 5,498,613 by Rodgers et al.,the content of which is herein incorporated by reference in its entirety.

Embodiments include a process for providing a target minimum (anti-thrombotic) effective amount of dipyridamole to be directly eluted into the vascular tissue from a drug- eluting implant surface. If an overstated assumption is made that, in order to be effective, all of the dipyridamole from a prescribed systemic dosage is required to be absorbed into a given cardiovascular region, an amount of drug to be absorbed for a given area of tissue can be calculated. Therefore, in accordance with an embodiment , the minimal dosage per area (μg/mm²) of vessel tissue wall of length L will be about half of this radius (r) multiplied by the prescribed systemic dosage (sd): μg sd - m¹ - L sd - r mm² 2ττr • L 2

In a stenting application, for example, the smallest diameter (and, thus, the highest ratio of tissue area to the volume of blood in the adjacent vessel segment) of a coronary vessel has a radius generally no greater than about 1.1 mm. Therefore, in accordance with an embodiment, a systemic dosage of between about .5 and 1.9 micrograms per milliliter of blood is translated into a steady-state tissue administration to actively maintain between about .000275 to .001 micrograms of dipyridamole per square millimeter of tissue surrounding the cylindrical form of the stent. A delivery system such as a dipyridamole-carrying polymer for effecting prescribed dosages for a given area of tissue can then be developed in accordance with an embodiment . The mixture of polymer to drug will depend on the area of tissue affected by the stent, the expanded drug-eluting surface area of the stent, the drug-eluting characteristics of the polymer, the drug-absorbing characteristics of the affected tissue, the targeted time period of application, and the half-life(s) of dipyridamole. A wide variety of delivery systems, including polymers, stents and stent sizes may be selected depending on the particular stenting application. Various delivery systems include polymer-based diffusion-controlled matrix systems widely marketed and sold, swelling-controlled release systems, and bioabsorbable systems. Studies can generally be performed for characterizing and adapting the elution profile of dipyridamole for a given delivery system.

Since dipyridamole has highly hydrophobic characteristics, a substantial amount of the eluted drug is predicted to be absorbed by surrounding tissue. Further studies can be performed for determining the precise tissue-absorption behavior of dipyridamole from a drug-eluting stent. Metabolism of the drug delivered intravenously includes three half-lives known to be about 3-4 minutes for a first period, 39 minutes for a second period, and about 15.5 hours for a third half-life period (see http://www.rxlist.com/cgi/generic3/aggrenox_cp.htm for the clinical pharmocology of the dipyridamole-based anti-thrombotic drug Aggrenox). Thus, during a substantial period of the "life" of the drug (at least about 10 hours), about a minimum of 12.5% of the absorbed dosage will remain active in the tissue. Thus, in accordance with an embodiment , a dosage level of at least about 8 times the targeted steady-state amount is delivered over each 10 hour period until about the end of the target therapy period. One critical period in which to address anti-thrombotic effects is about the first 7 days after deployment, an important period for promoting proper healing around the tissue of the stent, and is also during which period there is the highest potential for thrombosis.

Thus, in an embodiment , a rate of about at least 8 times .000275 to .001 micrograms (or .0022 to .008 micrograms) of dipyridamole is eluted per square millimeter of tissue surrounding the cylindrical form of the stent over about each 10 hour interval during the target period. In an embodiment , the target period is the first 7 or more days after deployment.

A certain amount of the drug will potentially not be absorbed (washed out) or not be evenly distributed within the targeted surrounding tissue, particularly within certain lesions resistive to diffusion (see "Handbook of Dmg-Eluting Stents," Serruys, P. W. and Gershlick, A.H., eds., Taylor & Francis, pp. 47-56 (2005), the entire contents of which is herein incorporated by reference). Additionally, a localized dosage moderately increased in relation to the proscribed systemic dosage is not known or expected to cause significant local or systemic adverse reactions, and will generally increase the anti-restenosis effect (e.g., see Figs. 3A-C & 4 and accompanying description of results). Therefore, in an embodiment , an increased elution rate of about 5 to 10 times more than what would be optimally targeted for absorption and even distribution is locally delivered over each 10 hour period until about the end of the target therapy period. In an embodiment, the target therapy period for the increased dosage is at least the first 3 days following placement of the stent, a period when adverse tissue growth can be particularly prolific.

Thus, in an embodiment , a rate of at least about 5 to 10 times .0022 to .008 micrograms (or at least about .01 to .08 micrograms) is eluted per square millimeter of tissue surrounding the cylindrical form of the stent over about each 10 hour interval after deployment. In an embodiment , a rate of between about .0022 to .008 micrograms per square millimeter or more, or between about .01 to .08 micrograms per square millimeter or more is eluted over about each 10 hour interval for least 7 or more consecutive days. In an embodiment , a rate of between .01 to .08 or more micrograms per square millimeter over each 10 hour interval is eluted over the first 3 days after stent deployment and between .0022 to .008 micrograms per square millimeter or more is eluted over each 10 hour interval during the subsequent 4 days.

Referring respectively to Figs. 3A, 3B, and 3C, cross-sectional views of Wistar rat aortas are shown from a pre-clinical study during which were placed a bare stainless steel stent, a stent coated with a dipyridamole-eluting polymer, and a stent coated with the same polymer without dypyridamole. Eighteen (18) stents (six of each type) were placed in the abdominal aortas of the rats for a period of 28 days after which the aortal segments were harvested and histologies performed. Fig. 2A is an illustrative side view of the basic geometry of a stent 50 in accordance with an embodiment and that of the stents used in the study. Fig. 2B is an illustrative transverse cross-sectional view of a strut 60 of the stent of Fig. 2A, taken along section lines I-I' of Fig. 2A. Further details of the stent design used in the study and other designs in accordance with other embodiments are more fully described in U.S. Patent Application No. 1 1/613,443, published as U.S. Patent Publication No. US2007/0173925A1, the contents of which is herein incorporated by reference. The stents used in the study were 9 mm in length and expanded to about 2.5 mm in diameter (from a crimped diameter of about 1 mm) within the aortas. In an embodiment , and in general accordance with the study, a polymer layer 80 with a dipyridamole matrix is coated over stent 50, and adhered to stent 50 with the aid of a tie-coat 70. The drug-eluting polymer used in the study (CardioTech International, Inc.'s Chronoflex AL polymer system) was of an aliphatic polycarbonate polyeurethane type combined with a tie-coat system for better adhering the drug-eluting polymer to the stainless steel substrate (embodiments of which are more fully described in U.S. Patent No. 5,254,662 and U.S. Patent Application No. 60/889,655 filed February 13, 2006, the contents of each which of which are herein incorporated by reference in their entirety). The dipyridamole (Sigma® brand animal-grade Dipyridamole, 98% TLC) was mixed in the polymer solution to about a 23% ratio of drug-to- polymer by weight. The polymer coating was applied to a thickness of about 10 microns while the stent was at a diameter of about 2 millimeters.

Referring to Figs. 1 A-IB, an elution profile is shown for dipyridamole with the same polymer system having a 30% drug-to-polymer ratio by weight, coated to a thickness of about 10 micrometers over three stents 18 millimeters (mm) in length (of a similar geometry to that placed in the rats), each roughly having a surface area of about 53 square millimeters. The stents were coated while at a diameter of about 2 millimeters, and expanded to a diameter of about 4 millimeters and placed in a 37° C saline solution for 28 days. Measurements of eluted drug were taken after about .5, 1, 3, 7, 14, and 28 days via spectroscopy. The elution profile indicates that the drug eluted (in reference to a surface, if present, directly surrounding the stent) would be at a rate of about .073 micrograms per square millimeter per 10 hour interval over the first 12 hours, about .061 micrograms per square millimeter per 10 hour interval over the next 12 hours, .016 micrograms per square millimeter per 10 hour period over the subsequent 2 days, .007 micrograms per square millimeter per 10 hour interval over the subsequent 4 days, and .004 micrograms per square millimeter per 10 hour interval over the subsequent 7 days.

Comparing Figs. 3A, 3B, and 3C, a reduction in neo-intimal growth was observed for the polymer-only stent (Fig. 3C) and an even further reduction was observed for the dipyridamole-eluting polymer (Fig. 3B) in comparison to the bare metal stent (Fig. 3A). Referring to Fig. 4, the neo-intimal growth around the 18 stents placed in the rats (6 of a bare metal surface, 6 ofa polymer-only surface, and 6 of a 23% dipyridamole-to-polymer coated surface) were measured and compared. The growth within the dipyridamole-eluting stents was reduced by about an average amount of 23% in comparison to the bare metal stents. The polymer by itself was observed to provide a reduction of neo-intimal growth of by an average amount of about 16% in comparison to the bare-metal stent. Based on prior studies, the improvements in biocompatibility of presently marketed metal surfaces (e.g., stainless steel, cobalt-chromium) alone will not likely be significant in comparison to the anti-restenotic or anti-thrombotic benefits of the above described embodiments of polymer and/or dipyridamole-eluting surfaces. Thus, in addition to providing anti-thrombotic benefits, dipyridamole-eluting delivery systems in accordance with embodiments of the invention can provide significant anti-stenotic benefits.

In addition to providing anti-thrombotic and anti-stenotic benefits, dipyridamole is also known to have much less toxicity than drugs used with well-known eluting systems (e.g., paclitaxel-eluting and sirolimus-eluting coatings). Dipyridamole does not act substantially as a cell-cycle inhibitor or anti-cancer agent such as, for example, paclitaxel and sirolimus. Thus, dipyridamole-eluting stents in accordance with embodiments of the invention can provide anti-stenotic and anti-thrombotic benefits in a single drug while not substantially interfering with the proper-healing of vessel wall tissue and, thus, can also reduce the likelihood of late-term thrombosis subsequent to stenting.

Claims

I claim:

1. A surface coating system for implantable devices, comprising: an implantable structure having a surface thereon; one or more coatings layered on said surface, said coatings comprising a surface layer, said surface layer is manufactured to elute, upon deployment of said implantable structure in a human, a therapeutically effective dosage of dipyridamole that significantly reduces the likelihood of at least one of thrombosis and restenosis along said implantable structure.

2. The surface coating system of claim 1, wherein said implantable structure is a stent.

3. The surface coating system of claim 1, wherein said effective dosage of dipyridamole maintains about .000275 to .001 micrograms of dipyridamole per square millimeter of tissue surface that directly encompasses the implantable structure.

4. The surface coating system of claim 1, wherein said surface layer elutes said effective dosage at a rate of between at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of a target therapy period.

5. The surface coating system of claim 4, wherein said surface layer elutes said effective dosage at a rate of between about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of the target therapy period.

6. The surface coating system of claim 4, wherein said target therapy period comprises at least the initial 7 consecutive days after deployment of said implantable structure.

7. The surface coating system of claim 4, wherein said surface layer elutes said effective dosage at a rate of between about .01 to .08 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval for at least a portion of said target therapv period.

8. The surface coating system of claim 7, wherein said at least a portion of said target therapy period comprises the initial 3 consecutive days after deployment of said implantable structure.

9. The surface coating system of claim 8, wherein said target therapy period comprises at least the initial 7 days after deployment of said implantable structure during which period at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area is eluted during each 10 hour interval.

10. The surface coating system of claim 1, wherein the surface of the implantable structure does not significantly elute any other therapeutically active agent other than said therapeutically effective dosage of dipyridamole.

11. A method of delivering an implantable device: providing an implantable structure having a surface thereon; placing said implantable structure into a living subject; eluting from the surface of the implantable structure a therapeutically effective dosage of dipyridamole, said dosage sufficient to significantly reduce the likelihood of at least one of thrombosis or restenosis along said implant structure.

12. The method of claim 11, wherein said implantable device is a stent.

13. The method of claim 11 , wherein said effective dosage of dipyridamole maintains about .000275 to .001 micrograms of dipyridamole per square millimeter of tissue surface directly encompassing the implantable structure.

14. The method of claim 11 , wherein eluting the therapeutically effective dosage comprises eluting at a rate of at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of a target therapy period.

15. The method claim 14, wherein eluting the therapeutically effective dosage comprises eluting at a rate of between about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of a target therapy period.

16. The method of claim 15, wherein said target therapy period comprises at least the initial 7 consecutive days after deployment of said implantable structure.

17. The method of claim 15, wherein the eluting a therapeutically effective dosage comprises eluting at a rate of at least about .01 to .08 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval for at least a portion of said target therapy period.

18. The method of claim 17, wherein said at least a portion of said target therapy period comprises the initial 3 consecutive days after deployment of said implantable structure.

19. The method of claim 18, wherein said target therapy period comprises at least the initial 7 days after deployment of said implantable structure during which at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area is eluted during each 10 hour interval.

20. The method of claim 11, wherein the surface of the implantable structure does not significantly elute any other therapeutically active agent other than said therapeutically effective dosage of dipyridamole.

21. A method of stenting a vessel comprising the steps of: providing a stent having a surface thereon; placing said stent into said vessel; eluting dipyridamole from the surface of the stent at a rate of least about .0022 to .008 micrograms of dipyridamole per square millimeter of inner vessel surface area surrounding the stent during each 10 hour interval for a target therapy period.

22. The method of claim 21 , wherein the target therapy period includes the initial 7 days after deployment.

23. The method of claim 21, wherein dipyridamole is eluted at a rate of about .01 to .08 micrograms of dipyridamole per square millimeter of inner vessel surface area surrounding the stent during each 10 hour interval for a period of at least 3 days.

24. An implantable device comprising: a substrate; and a polymer-based layer coating said substrate, said polymer-based layer having a dipyridamole- to-polymer ratio of between about 20% and 30% by weight.

25. The implantable device of claim 24, wherein said polymer-based layer has a dipyridamole-to-polymer ratio of about 30% or more by weight.